AUTHOR=Liao Dan , Zeng Saitian , Li Cuifen , Yao Yuhong , Guo Min , Cui Yejia , Huang Haohai 

TITLE=FOXK2 regulates fatty acid metabolism and promotes cervical cancer progression by activating the mTOR/DRP1 signaling axis

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=Volume 13 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2025.1615454

DOI=10.3389/fcell.2025.1615454

ISSN=2296-634X

ABSTRACT=BackgroundCervical cancer is a prevalent malignancy among women, and its pathogenesis is highly complex. Lipid metabolism plays a crucial role in providing sufficient metabolites and energy for the rapid proliferation and progression of tumors, significantly influencing the advancement of cervical cancer. However, the specific lipid metabolism mechanisms remain to be thoroughly investigated. This study aims to elucidate the lipid metabolism mechanisms by which FOXK2 promotes the progression of cervical cancer.MethodsFOXK2 overexpression and knockdown cell lines were constructed, The cell activity and invasion were evaluated using CCK8, Edu, transwell, and flow cytometry. The oxygen consumption rate (OCR) values were detected by the XFe96 analyzer. The expression of fatty acid oxidation (FAO) related genes was analyzed by WB and qRT-PCR. The binding of FOXK2 to mTOR and mTOR to DRP1 was detected by co-immunoprecipitation (CoIP). Ultimately FOXK2-knockdown cells were applied to construct the Xenograft tumors in nude mice, and the relevant experiments were verified in vivo.ResultsIn vitro experiments, our findings demonstrated that FOXK2 enhances the proliferation and invasive capabilities of cervical cancer cells. FOXK2 expression was found to upregulate the expression of CPT1A, a key enzyme involved in FAO while downregulating the expression of critical lipogenic enzymes ACC1 and FASN. FOXK2 was shown to increase the phosphorylation levels of mTOR and interact with both mTOR and DRP1. Mechanistically, FOXK2 promotes lipid metabolic reprogramming in cervical cancer by interacting with the mTOR/DRP1 signaling axis. Furthermore, the role of FOXK2 in regulating lipid metabolism reprogramming in cervical cancer and its effects on the mTOR/DRP1 axis were validated in xenograft tumor models.ConclusionFOXK2 interacts with and phosphorylates mTOR, which facilitates the expression of DRP1 and activates the mTOR/DRP1 signaling axis. This activation regulates lipid metabolic reprogramming and promotes the progression of cervical cancer.